There are many naturally-occurring organic compounds which are in a form of optically active substances. Among the compounds having physiological activities, a desirable activity is frequently present in only one type of their optical isomers. Furthermore, it is also known that the other optical isomer without the desirable activity does not have a useful physiological activity for living organisms, rather, sometimes it has a toxicity for living organisms. Accordingly, as a safe method for the synthesis of pharmaceuticals, development of a method for synthesizing objective compounds, or optically active compounds having a high optical purity as intermediates of the objective compounds, has been desired.
Optically active alcohols are useful as asymmetric sources for synthesizing various optically active substances. In general, optically active alcohols are produced by optical resolution of racemic bodies, or by asymmetric synthesis using a biological catalyst or an asymmetric metal complex as a catalyst. In particular, production of optically active alcohols by asymmetric synthesis is considered to be indispensable for producing a large amount of optically active alcohols.
Optically active fluoroalcohols are one of the optically active alcohols that are industrially useful as synthetic intermediates of optically-active and physiologically-active compounds employed for pharmaceuticals and agrochemicals, or as synthetic intermediates of liquid crystal materials. For example, optically active 1,1,1-trifluoro-2-propanol is a synthetic intermediate of glycine transport inhibitors, and is effective for the treatment of mental diseases such as Alzheimer's dementia, mania, and depression (Patent Literature 1), and is also employed as synthetic intermediates of p38 MAP kinase inhibitors (Non Patent Literature 1). In addition, optically active 1,1,1-trifluoro-2-butanol is used as a synthetic intermediate of antiferroelectric liquid crystal compounds, realizing high-speed responsiveness (Patent Literature 2).
Synthetic methods of optically active fluoroalcohols are roughly classified into methods employing microorganisms and chemical methods. As methods employing microorganisms, there are reports on a method to use selective hydrolysis of esters, a method for asymmetric reduction of fluoroketones and so on. Examples of chemical methods include optical resolution, asymmetric hydrogenation, and asymmetric reduction. These methods are exemplified below.
As an example of employing selective hydrolysis of esters by microorganisms, there is a report on a method to synthesize optically active 1,1,1-trifluoro-2-butanol by enantioselective alcoholysis of corresponding ester with lipase (Patent Literature 2). With this method, the objective substance is obtained by extraction of a product using methylene chloride; however, a half of the raw material used becomes unnecessary, which is inefficient. In addition, there exists a problem of difficulty in complete distillation of a solvent away, as well as a problem of low yield.
As an example of reduction using microorganisms, a method for obtaining 1,1,1-trifluoro-2-propanol by reaction of 1,1,1-trifluoro acetone with a baker's yeast in a buffer solution has been known (Patent Literature 1), in which for the recovery of the objective substance from the buffer solution, extraction with an organic solvent or direct distillation is used. However, in the case of extraction with an organic solvent, separation from the organic solvent used is difficult due to the fairly low boiling point of 82° C. of alcohol. In the case of distillation from a buffer solution, since alcohol with a low concentration in the buffer solution are to be distilled, it is difficult to obtain the objective alcohol with a high yield.
As an example of kinetic resolutions, the following method has been known: racemic (trifluoromethyl)ethylene oxide is enantioselectively hydrated under the presence of a cobalt-salen complex catalyst, then (trifluoromethyl)ethylene oxide which remains without being reacted is separated to obtain optically active (trifluoromethyl ethylene oxide); then, by reacting this with hydrogenated lithium aluminum, optically active 1,1,1-trifluoro-2-propanol is obtained. However, this can hardly be an efficient synthetic method by separation, because a half of the raw material used becomes unnecessary (Non Patent Literature 2).
As an example of using asymmetric hydrogenation catalysts, a method wherein 1,1,1-trifluoroacetone is subjected to hydrogenated pressurization under the presence of an asymmetric hydrogenation catalyst has been known (Patent Literature 3). However, high-pressure hydrogen of 40 MPa or more must be used, requiring a corresponding high-pressure reactor; thus, it is not an easy method.
As an example of asymmetric reduction using an organic substance as a hydrogen source, the following method has been known: 1,1,1-trifluoroacetone having a halogen atom at position 3 is reduced by an optically-active borane reducing agent to synthesize optically active 3-halo-1,1,1-trifluoro-2-propanol, and this substance is converted into optically active (trifluoromethyl)ethylene oxide by the reaction with sodium hydroxide, then this is treated with lithium aluminum hydride to obtain optically active 1,1,1-trifluoro-2-propanol. In this method however, an expensive optically-active substance is used at a stoichiometric amount, and the reaction is a multi-step reaction; thus, this is hardly said to be an efficient method (Non Patent Literature 3).
Focusing on asymmetric reduction catalysts which enable synthesis of optically active alcohols from corresponding ketones via one-step reaction with which no special reactor is required, asymmetric ruthenium, rhodium and indium catalysts having sulfonyl diamine as a ligand have been known to be useful asymmetric reduction catalysts (Patent Literature 4, Patent Literature 5). As an example of synthesis of fluoroalcohols using such method, a case wherein 1,1,1-trifluoroketone is asymmetrically reduced in formic acid/triethylamine under the presence of an asymmetric ruthenium catalyst has been known (Non Patent Literature 4). However, with this method, a post-treatment to remove formic acid and triethylamine by washing with water is necessary after the reaction solution is dissolved in a solvent. Because of this process, in cases of alcohols having a boiling point close to that of a solvent, separation from the solvent becomes difficult in some cases. In fact, in this literature, only a case of 1,1,1-trifluoro-2-octanone having a fairly high boiling point with which solvent extraction and washing with water are possible is described as an example of the reaction of aliphatic ketones, and synthesis of fluoroalcohols having a low boiling point which easily dissolve in water, such as 1,1,1-trifluoro-2-propanol, is not at all mentioned.
Meanwhile, in hydrogen-transfer type asymmetric reduction of ketones using ruthenium, iridium or rhodium catalyst having the above sulfonyl diamine as a ligand, the following 2-phase reduction has been known (Non Patent Literature 5, Non Patent Literature 6); namely, in water as a solvent, reaction is carried out in a state of separation of 2 phases of water-organic layers, using formate as a hydrogen source; and it has been reported that pH affects the catalyst reaction. For example, when reduction is carried out using formic acid/triethylamine as a hydrogen source, and when the amounts of formic acid and triethylamine are changed to change the pH value of the reaction solution, then the reaction rate and optical purity of the alcohol obtained are known to be affected (Non Patent Literature 6). However, in this literature, only a synthetic method of optically active aromatic alcohols using aromatic ketones as a substrate has been described, and synthesis of optically active aliphatic fluoroalcohols such as 1,1,1-trifluoro-2-propanol using an aliphatic ketone having a fluorine atom at α position as a substrate has not been mentioned.